The intake of food and its conversion in the body is an essential part of life for all living creatures. Therefore, deviations in the intake and conversion of food generally lead to problems and also illness. The changes in the lifestyle and nutrition of humans, particularly in industrialized countries, have promoted morbid overweight (also known as corpulence or obesity) in recent decades. In affected people, obesity leads directly to restricted mobility and a reduction in the quality of life. There is the additional factor that obesity often leads to other diseases such as, for example, diabetes, dyslipidemia, high blood pressure, arteriosclerosis, and coronary heart disease. Moreover, high bodyweight alone puts an increased strain on the support and mobility apparatus, which can lead to chronic pain and diseases such as arthritis or osteoarthritis. Thus, obesity is a serious health problem for society.
The term obesity means an excess of adipose tissue in the body. In this connection, obesity is fundamentally to be seen as the increased level of fatness which leads to a health risk. There is no sharp distinction between normal individuals and those suffering from obesity, but the health risk accompanying obesity is presumed to rise continuously as the level of fatness increases. For simplicity's sake, in the present invention, individuals with a Body Mass Index (BMI), which is defined as the bodyweight measured in kilograms divided by the height (in meters) squared, above a value of 25 and more particularly above 30, are preferably regarded as suffering from obesity.
Apart from physical activity and a change in nutrition, there is currently no convincing treatment option for effectively reducing bodyweight. As obesity is a major risk factor in the development of serious and even life-threatening diseases, however, it is all the more important to have access to pharmaceutical active substances for the prevention and/or treatment of obesity. One approach which has been proposed very recently is the therapeutic use of MCH antagonists (cf. inter alia WO 01/21577 and WO 01/82925).
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is synthesized predominantly in the hypothalamus in mammals and from there travels to other parts of the brain by the projections of hypothalamic neurons. Its biological activity is mediated in humans through two different glycoprotein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, namely the MCH receptors 1 and 2 (MCH-1R, MCH-2R).
Investigations into the function of MCH in animal models have provided good indications for a role of the peptide in regulating the energy balance, i.e., changing metabolic activity and food intake. D. Qu, et al., A role for melanin-concentrating hormone in the central regulation of feeding behavior, Nature, 1996, 380(6571): pp. 243-7; M. Shimada, et al., Mice lacking melanin-concentrating hormone are hypophagic and lean, Nature, 1998, 396(6712): pp. 670-4. For example, after intraventricular administration of MCH in rats, food intake was increased compared with control animals. Additionally, transgenic rats which produce more MCH than control animals, when given a high-fat diet, responded by gaining significantly more weight than animals without an experimentally altered MCH level. It was also found that there is a positive correlation between phases of increased desire for food and the quantity of MCH mRNA in the hypothalamus of rats. However, experiments with MCH knock-out mice are particularly important in showing the function of MCH. Loss of the neuropeptide results in lean animals with a reduced fat mass, which take in significantly less food than control animals.
The anorectic effects of MCH are presumably mediated in rodents through the G-Galpha i-coupled MCH-1R [B. Borowsky, et al., Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist, Nat Med, 2002, 8(8): pp. 825-30; Y. Chen, et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity, Endocrinology, 2002, 143(7): pp. 2469-77; D. J. Marsh, et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA, 2002, 99(5): pp. 3240-5; S. Takekawa, et al., T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002, 438(3): pp. 129-35.], as, unlike primates, ferrets, and dogs, no second MCH receptor subtype has hitherto been found in rodents. After losing the MCH-1R, knock-out mice have a lower fat mass, an increased energy conversion and, when fed on a high fat diet, do not put on weight, compared with control animals. Another indication of the importance of the MCH system in regulating the energy balance results from experiments with a receptor antagonist (SNAP-7941). B. Borowsky, et al., Nat Med, 2002, 8(8): pp. 825-30. In long term trials, the animals treated with the antagonist lose significant amounts of weight.
In addition to its anorectic effect, the MCH-1R antagonist SNAP-7941 also achieves additional anxiolytic and antidepressant effects in behavioral experiments on rats. B. Borowsky, et al., Nat Med, 2002, 8(8): pp. 825-30. Thus, there are clear indications that the MCH-MCH-IR system is involved not only in regulating the energy balance but also in affectivity.
In the patent literature certain amine compounds are proposed as MCH antagonists. Thus, WO 01/21577 (Takeda) describes compounds of formula
wherein Ar1 denotes a cyclic group, X denotes a spacer, Y denotes a bond or a spacer, Ar denotes an aromatic ring which may be fused with a non-aromatic ring, R1 and R2 independently of one another denote H or a hydrocarbon group, while R1 and R2 together with the adjacent N atom may form an N-containing hetero ring and R2 with Ar may also form a spirocyclic ring, and R together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity.
Moreover WO 01/82925 (Takeda) also describes compounds of formula
wherein Ar1 denotes a cyclic group, X and Y represent spacer groups, Ar denotes an optionally substituted fused polycyclic aromatic ring, R1 and R2 independently of one another represent H or a hydrocarbon group, while R1 and R2 together with the adjacent N atom may form an N-containing heterocyclic ring and R2 together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity, inter alia.
WO 2004/024702 proposes carboxylic acid amide compounds of formula I
wherein Y, A, and B may represent cyclic groups and X, Z, and W may denote bridges or bonds, as MCH-antagonists.
WO 04/039780 A1 describes alkyne compounds of formula I
wherein Y, A, and B may denote cyclic groups and X, Z, and W may denote bridges or bonds, as MCH-antagonists.
WO 04/039764 A1 describes amide compounds of formula I
wherein Y, A, and B may denote cyclic groups and X denotes an alkylene bridge, Z denotes a bridge or bond and W is selected from the group comprising —CR6aR6b—O, —CR7a═CR7c, —CR6aR6b—NR8, —CR7aR7b—CR7cR7d—, and —NR8—CR6aR6b—, as MCH-antagonists.
The aim of the present invention is to identify new alkyne compounds, particularly those which are especially effective as MCH antagonists. The invention also sets out to provide new alkyne compounds which can be used to influence the eating habits of mammals and achieve a reduction in body weight, particularly in mammals, and/or prevent an increase in body weight.
The present invention further sets out to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally connected to MCH. In particular, the aim of this invention is to provide pharmaceutical compositions for the treatment of metabolic disorders such as obesity and/or diabetes as well as diseases and/or disorders which are associated with obesity and diabetes. Other objectives of the present invention are concerned with demonstrating advantageous uses of the compounds according to the invention. The invention also sets out to provide a process for preparing the amide compounds according to the invention. Other aims of the present invention will be immediately apparent to the skilled man from the foregoing remarks and those that follow.
In a first aspect, the present invention relates to alkyne compounds selected from the list comprising:
No.Name1.1(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopropylmethylamine1.2(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylamine1.3(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylmethylamine1.45-(4-chlorophenyl)-2-{4-[2-((S)-2-methoxymethylpyrrolidin-1-yl)ethoxy]-3-methylphenylethynyl}pyridine1.55-(4-chlorophenyl)-2-{4-[2-((R)-2-methoxymethylpyrrolidin-1-yl)ethoxy]-3-methylphenylethynyl}pyridine1.61-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-4-trifluoromethylpiperidin-4-ol1.71-[1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)piperidin-4-yl]-2,2,2-trifluoroethanol1.81-[1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)piperidin-4-yl]-2,2,2-trifluoroethanone1.9(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclohexylcyclopentylamine1.10(3S,4R)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-4-trifluoromethylpiperidin-3,4-diol1.11(3R,4S)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-4-trifluoromethylpiperidin-3,4-diol1.122-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethylamino)-2-methylpropan-1-ol1.13[1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl-amino)cyclopentyl]methanol2.1(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclohexyl-cyclopropylmethylamine2.2(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)dicyclopentylamine2.3(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentyl-cyclopropylmethylamine2.4(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylmethyl-cyclopropylmethylamine2.5(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentyl-cyclopentylmethylamine2.6(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclohexylcyclopentylmethylamine3.12-[(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylamino]ethanol3.23-[(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylamino]propan-1-ol3.33-[(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentyl-methylamino]propan-1-ol3.42-[(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopentylmethylamino]ethanol4.2(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)cyclohexyl-cyclopropylmethylamine4.31-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-trifluoromethylpiperidin-4-ol4.41-[1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)piperidin-4-yl]-2,2,2-trifluoroethanol4.51-[1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)piperidin-4-yl]-2,2,2-trifluoroethanone4.6(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)cyclopropyl-methylpropylamine4.7(3S,4R)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-trifluoromethylpiperidin-3,4-diol4.8(3R,4S)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-trifluoromethylpiperidin-3,4-diol4.98-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-3-methyl-8-azabicyclo[3.2.1]octan-3-ol4.108-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-3-ethyl-8-azabicyclo[3.2.1]octan-3-ol4.11exo-8-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-3-trifluoromethyl-8-azabicyclo[3.2.1]octan-3-ol4.12endo-8-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-3-trifluoromethyl-8-azabicyclo[3.2.1]octan-3-ol4.13(R)-2-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethylamino)propan-1-ol4.142-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethylamino)-2-methylpropan-1-ol4.15[1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethylamino)cyclopentyl]methanol5.1(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)cyclopentyl-cyclopropylmethylamine6.13-[(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)cyclopropyl-methylamino]propan-1-ol7.22-[4-(2-azetidin-1-ylethoxy)phenylethynyl]-5-(4-chlorophenyl)-3-fluoropyridine7.35-(4-chlorophenyl)-3-fluoro-2-{4-[2-((S)-2-methoxymethylpyrrolidin-1-yl)ethoxy]phenylethynyl}pyridine7.48-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)-8-azabicyclo[3.2.1]octan-3-ol7.5[1-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)piperidin-4-yl]methanol7.61-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)piperidin-3-ol7.7(3R,4S)-1-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-3,4-diol7.81-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)-4-trifluoromethylpiperidin-4-ol7.91-[(S)-1-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)pyrrolidin-2-yl]cyclopropanol8.1[(S)-1-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]-2-methylphenoxy}ethyl)pyrrolidin-2-yl]methanol8.25-(4-chlorophenyl)-3-fluoro-2-{4-[2-((S)-2-methoxymethylpyrrolidin-1-yl)ethoxy]-3-methylphenylethynyl}pyridine8.35-(4-chlorophenyl)-3-fluoro-2-{3-methyl-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl-ethynyl}pyridine8.48-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-8-azabicyclo[3.2.1]octan-3-ol8.51-[(S)-1-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]-2-methylphenoxy}ethyl)pyrrolidin-2-yl]cyclopropanol8.61-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-4-methylpiperidin-4-ol9.1[(S)-1-(2-{2-bromo-4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)pyrrolidin-2-yl]methanol9.21-[(S)-1-(2-{2-bromo-4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)pyrrolidin-2-yl]cyclopropanol9.32-{3-bromo-4-[2-((S)-2-methoxymethylpyrrolidin-1-yl)ethoxy]phenylethynyl}-5-(4-chlorophenyl)-3-fluoropyridine9.41-(2-{2-bromo-4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-4-ol9.52-{3-bromo-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}-5-(4-chlorophenyl)-3-fluoropyridine9.68-(2-{2-bromo-4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)-8-azabicyclo[3.2.1]octan-3-ol10.15-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-1-[2-(4-methylpiperidin-1-yl)ethyl]-1H-indazole10.2[(S)-1-(2-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]indazol-1-yl}ethyl)pyrrolidin-2-yl]methanol10.31-(2-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]indazol-1-yl}ethyl)-4-methylpiperidin-4-ol10.45-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-1-[2-(2,6-dimethylpiperidin-1-yl)ethyl]-1H-indazole11.15-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]-3-vinylphenylethynyl}pyridine11.21-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-vinylphenoxy}ethyl)-4-methylpiperidin-4-ol11.3[(S)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-vinylphenoxy}ethyl)pyrrolidin-2-yl]methanol11.45-(4-chlorophenyl)-2-{4-[2-(4,4-dimethylpiperidin-1-yl)ethoxy]-3-vinylphenylethynyl}pyridine12.15-(4-chlorophenyl)-2-{3-isopropenyl-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine12.2[(S)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-isopropenylphenoxy}ethyl)pyrrolidin-2-yl]methanol12.31-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-isopropenylphenoxy}ethyl)-4-methylpiperidin-4-ol12.45-(4-chlorophenyl)-2-{4-[2-(4,4-dimethylpiperidin-1-yl)ethoxy]-3-isopropenylphenylethynyl}pyridine12.51-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-isopropenylphenoxy}ethyl)-4-trifluoromethylpiperidin-4-ol13.11-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl}ethanone13.21-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-((S)-2-hydroxymethylpyrrolidin-1-yl)ethoxy]phenyl}ethanone13.31-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy]phenyl}ethanone13.41-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4,4-dimethylpiperidin-1-yl)ethoxy]phenyl}ethanone13.51-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-hydroxy-4-trifluoromethylpiperidin-1-yl)ethoxy]phenyl}ethanone14.15-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]benzaldehyde-O-methyloxime14.25-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-((S)-2-hydroxymethylpyrrolidin-1-yl)ethoxy]benzaldehyde-O-methyloxime14.35-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-hydroxypiperidin-1-yl)ethoxy]benzaldehyde-O-methyloxime14.45-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzaldehyde-O-methyloxime14.55-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzaldehyde-O-methyloxime15.15-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]benzaldehydeoxime15.25-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-((S)-2-hydroxymethylpyrrolidin-1-yl)ethoxy]benzaldehydeoxime15.35-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-hydroxypiperidin-1-yl)ethoxy]benzaldehydeoxime15.45-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzaldehydeoxime15.55-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzaldehydeoxime16.13-bromo-5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine17.15-(4-chlorophenyl)-3-methyl-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine18.13-methyl-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}-5-p-tolylpyridine19.15-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-ylamine20.1{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenyl}-[2-(4-methylpiperidin-1-yl)ethyl]amine21.13-chloro-5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine21.2[(S)-1-(2-{4-[3-chloro-5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)pyrrolidin-2-yl]methanol21.31-(2-{4-[3-chloro-5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-4-ol22.15-(4-chlorophenyl)-2-[2-(4-methylpiperidin-1-ylmethyl)benzo[b]thiophen-5-ylethynyl]pyridine22.2((S}-1-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]benzo[b]thiophen-2-ylmethyl}pyrrolidin-2-yl)methanol22.31-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]benzo[b]thiophen-2-ylmethyl}-4-methylpiperidin-4-ol22.41-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]benzo[b]thiophen-2-ylmethyl}-4-trifluoromethylpiperidin-4-ol23.15-(4-chlorophenyl)-2-{3-methyl-4-[3-(4-methylpiperidin-1-yl)propyl]phenylethynyl}pyridine24.15-(4-chlorophenyl)-2-[3-ethyl-4-(2-pyrrolidin-1-ylethoxy)phenylethynyl]pyridine25.14-(6-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-yl)benzaldehyde26.11-[5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-ylethoxy)phenyl]ethanol27.11-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl}ethanol28.1{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]thiophen-3-yl}-[2-(4-methylpiperidin-1-yl)ethyl]amine29.15-(4-difluoromethylphenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine30.15-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-ylethoxy)benzylamine31.1N-(5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-yl)acetamide32.16-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methyl-2-(4-methylpiperidin-1-ylmethyl)quinoline33.15-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-ylethoxy)phenol34.15-(4-chlorophenyl)-2-[3-propoxy-4-(2-pyrrolidin-1-ylethoxy)phenylethynyl]pyridine34.25-(4-chlorophenyl)-2-[3-ethoxy-4-(2-pyrrolidin-1-ylethoxy)phenylethynyl]pyridine35.15-(4-chlorophenyl)-2-[3-isopropoxy-4-(2-pyrrolidin-1-ylethoxy)phenylethynyl]pyridine36.1(3-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]pyridin-2-yl}propyl)-4-methylpiperidine37.1tert-butyl (S)2-({4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenylamino}methyl)pyrrolidine-1-carboxylate38.12-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}-N,N-diethylbenzamide39.1cis-4-methyl-1-(6-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-yl)cyclohexanol40.1trans-4-methyl-1-(6-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-yl)cyclohexanol41.11-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl}-2,2,2-trifluoroethanol42.1{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}-(S)-1-pyrrolidin-2-ylmethylamine43.1(5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-yl)methylamine44.1(5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-yl)dimethylamine45.15-(4-methylcyclohex-1-enyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine46.1N'-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]pyridin-2-yl}-N,N-bis-cyclopropylmethylethan-1,2-diamine47.14-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}-1-cyclopropylmethylpiperidin-4-olincluding the tautomers, the diastereomers, the enantiomers, the mixtures thereof, and the salts thereof.
Thus, the first object of the present invention also includes alkyne compounds selected from the list comprising:
No.Name1.141-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-4-isopropylpiperidin-4-ol1.15(1R,3R,5S)-8-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-3-methyl-8-azabicyclo[3.2.1]octan-3-ol1.16(1R,3R,5S)-8-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-3-ethyl-8-azabicyclo[3.2.1]octan-3-ol1.17(1R,3S,5S)-8-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-3-trifluoromethyl-8-azabicyclo[3.2.1]octan-3-ol1.18(1R,3R,5S)-8-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-3-trifluoromethyl-8-azabicyclo[3.2.1]octan-3-ol1.191-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)-4-ethylpiperidin-4-ol4.161-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-isopropylpiperidin-4-ol4.171-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-ethylpiperidin-4-ol48.11-(2-{4-[5-(4-chlorophenyl)pyrazin-2-ylethynyl]phenoxy}ethyl)-4-trifluoromethylpiperidin-4-ol48.21-(2-{4-[5-(4-chlorophenyl)pyrazin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-4-ol48.32-(4-chlorophenyl)-5-{4-[2-(4,4-dimethylpiperidin-1-yl)ethoxy]phenylethynyl}pyrazine48.42-(4-chlorophenyl)-5-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyrazine48.5(2-{4-[5-(4-chlorophenyl)pyrazin-2-ylethynyl]phenoxy}ethyl)cyclopentylamine48.61-(2-{4-[5-(2,4-dichlorophenyl)pyrazin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-4-ol48.71-(2-{4-[5-(4-chloro-2-methylphenyl)pyrazin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-4-ol49.13-fluoro-5-(4-methylcyclohex-1-enyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine49.21-(2-{4-[3-fluoro-5-(4-methylcyclohex-1-enyl)pyridin-2-ylethynyl]phenoxy}ethyl)-4-methylpiperidin-4-ol50.1(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}ethyl)cyclopentylamine50.21-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}ethyl)-4-methylpiperidin-4-ol50.35-(4-chlorophenyl)-2-{4-[2-(4,4-dimethylpiperidin-1-yl)ethyl]phenylethynyl}pyridine50.45-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethyl]phenylethynyl}pyridine50.55-(4-chlorophenyl)-2-{3-methyl-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylethynyl}pyridine51.1(5-{4-[5-(4-chlorophenyl)pyridin-2-yl]but-3-inyl}pyridin-2-yl)isopropylamineincluding the tautomers, the diastereomers, the enantiomers, the mixtures thereof, and the salts thereof.
Thus, the invention also relates to the compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids.
In a second aspect, the present invention relates to alkyne compounds selected from the list comprising:
No.Name4.1[(S)-1-(2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenoxy}ethyl)pyrrolidin-2-yl]methanol7.1[(S)-1-(2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethyl)pyrrolidin-2-yl]methanoland the salts thereof.
Thus, the invention also relates to the compounds in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids.
The compounds according to the present invention, including the physiologically acceptable salts, are especially effective, compared with known, structurally similar compounds, as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit very good affinity in MCH receptor binding studies. In addition, the compounds according to the invention have a high to very high selectivity with regard to the MCH receptor. Generally the compounds according to the invention have low toxicity, they are well absorbed by oral route and have good intracerebral transitivity, particularly brain accessibility.
The subject of the invention also includes the compounds according to the invention, including their salts, wherein one or more hydrogen atoms are replaced by deuterium.
This invention also includes the physiologically acceptable salts of the alkyne compounds according to the invention as described above and hereinafter.
Also covered by this invention are compositions containing at least one alkyne compound according to the invention and/or a salt according to the invention optionally together with one or more physiologically acceptable excipients.
Also covered by this invention are pharmaceutical compositions containing at least one alkyne compound according to the invention and/or a salt according to the invention optionally together with one or more inert carriers and/or diluents.
This invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for influencing the eating behavior of a mammal.
The invention further relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for reducing the body weight and/or for preventing an increase in the body weight of a mammal.
The invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition with an MCH receptor-antagonistic activity, particularly with an MCH-1 receptor-antagonistic activity.
This invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.
A further object of this invention is the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa, and hyperphagia.
The invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of diseases and/or disorders associated with obesity, particularly diabetes, especially type II diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis, and gonitis.
In addition, the present invention relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia, and hormonal disorders.
The invention also relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of urinary problems, such as, for example, urinary incontinence, overactive bladder, urgency, nycturia, and enuresis.
The invention further relates to the use of at least one alkyne compound according to the invention and/or a salt according to the invention for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of dependencies and/or withdrawal symptoms.
The invention further relates to processes for preparing for preparing a pharmaceutical composition according to the invention, characterized in that at least one alkyne compound according to the invention and/or a salt according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
The invention also relates to a pharmaceutical composition containing a first active substance which is selected from the alkyne compounds according to the invention and/or the corresponding salts as well as a second active substance which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of dyslipidemia or hyperlipidemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and/or diluents.
The starting materials and intermediate products used in the synthesis according to the invention and the actual methods of synthesis described are also a subject of this invention.